title: Leucine-rich repeat kinase 2 (LRRK2)-deficient rats exhibit renal tubule injury and perturbations in metabolic and immunological homeostasis.
abstract: Genetic evidence links mutations in the LRRK2 gene with an increased risk of Parkinson's disease, for which no neuroprotective or neurorestorative therapies currently exist. While the role of LRRK2 in normal cellular function has yet to be fully described, evidence suggests involvement with immune and kidney functions. A comparative study of LRRK2-deficient and wild type rats investigated the influence that this gene has on the phenotype of these rats. Significant weight gain in the LRRK2 null rats was observed and was accompanied by significant increases in insulin and insulin-like growth factors. Additionally, LRRK2-deficient rats displayed kidney morphological and histopathological alterations in the renal tubule epithelial cells of all animals assessed. These perturbations in renal morphology were accompanied by significant decreases of lipocalin-2, in both the urine and plasma of knockout animals. Significant alterations in the cellular composition of the spleen between LRRK2 knockout and wild type animals were identified by immunophenotyping and were associated with subtle differences in response to dual infection with rat-adapted influenza virus (RAIV) and Streptococcus pneumoniae. Ontological pathway analysis of LRRK2 across metabolic and kidney processes and pathological categories suggested that the thioredoxin network may play a role in perturbing these organ systems. The phenotype of the LRRK2 null rat is suggestive of a complex biology influencing metabolism, immune function and kidney homeostasis. These data need to be extended to better understand the role of the kinase domain or other biological functions of the gene to better inform the development of pharmacological inhibitors.
authors.affiliation: Nonclinical Safety Evaluation, Elan Pharmaceuticals Inc., South San Francisco, California, United States of America.
authors.forename: Daniel
authors.initials: D
authors.lastname: Ness
authors.forename: Zhao
authors.initials: Z
authors.lastname: Ren
authors.forename: Shyra
authors.initials: S
authors.lastname: Gardai
authors.forename: Douglas
authors.initials: D
authors.lastname: Sharpnack
authors.forename: Victor J
authors.initials: VJ
authors.lastname: Johnson
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Brennan
authors.forename: Elizabeth F
authors.initials: EF
authors.lastname: Brigham
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Olaharski
mesh_terms: D000818:Animals; D000914:Antibodies, Viral / Q000097:blood; D001798:Blood Proteins / Q000378:metabolism; D004847:Epithelial Cells / Q000473:pathology; D055786:Gene Knockout Techniques; D053263:Gene Regulatory Networks; D006706:Homeostasis; D056724:Immunity, Humoral; D016130:Immunophenotyping; D007684:Kidney Tubules / Q000002:abnormalities / Q000473:pathology*; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D008297:Male; D009975:Orthomyxoviridae / Q000276:immunology; D009976:Orthomyxoviridae Infections / Q000276:immunology; D011018:Pneumonia, Pneumococcal / Q000276:immunology; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency* / Q000235:genetics; D051381:Rats; D013296:Streptococcus pneumoniae / Q000276:immunology; D015430:Weight Gain / Q000235:genetics
chemical_list: D000914:Antibodies, Viral; D001798:Blood Proteins; C547428:LRRK2 protein, rat; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D017346:Protein Serine-Threonine Kinases